Continuous production of active pharmaceutical ingredients

ABSTRACT

The present invention is directed to a method of producing active pharmaceutical ingredients (APIs). The method includes subjecting a reaction mixture with an API precursor to solvent extraction to produce a reactant stream with the API precursor. The method includes concentrating the API precursor in the reactant stream using at least one membrane. The method includes carrying out a reaction in a membrane reactor. The method includes separating the API precursor from the reaction stream using a separator. The method includes crystallizing the API precursor using a crystallizer to produce APIs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 63/123,172, which was filed on Dec. 9, 2020. The entirecontent of the foregoing provisional patent application is incorporatedherein by reference.

BACKGROUND

Active pharmaceutical ingredients (APIs) are traditionally produced bybatch chemical synthesis processes. Some APIs are beginning to beproduced by continuous manufacturing. Batch chemical synthesis processesmay involve a large number of synthesis steps (e.g., as many as 20synthesis steps). Such batch processes can involve large batch volumesand considerable hold time between steps. In some instances, a largeamount of product loss may occur if the quality of the resulting productis affected during the processing steps. Continuous manufacturingmethods generally involve a number of synthesis steps. (See, e.g.,Kuehn, S., Pharmaceutical manufacturing: Current trends and what's next,CEP, p. 23-29, December 2018). The volume of material moving through acontinuous manufacturing process is generally quite small (as comparedto batch chemical synthesis processes) and the quality of the resultingproduct can be monitored on a continuous basis during the process.

FIG. 1 is a schematic of an exemplary traditional continuouspharmaceutical production sequence of reactors and separators. Inparticular, FIG. 1 illustrates one traditional multistep continuous APIsynthesis process. The process or sequence illustrated in FIG. 1 can beperformed by a system 10 including a mixer 12, a first reactor 14, afirst heat exchanger 16, a first solvent separator 18, a second reactor20, a second heat exchanger 22, a second solvent separator 24, and acrystallizer 26. The system 10 can include a number of such sequencesdepending on the number of reaction/synthesis steps of the process. Eachsynthesis step in API manufacturing essentially includes a reaction stepfollowed by work-up such that the next synthesis step can beimplemented. The process continues with a number of consecutive reactionsteps followed ultimately by isolation and purification. Generally,crystallization is the process used for purification, followed byvarious steps for oral dosage-form manufacturing. The chemical synthesisreaction step in a reactor may be preceded by mixing and is generallyfollowed by a separator, filter and/or an evaporator/distillationdevice. In addition, there may be heating or cooling before, during,and/or after the synthesis step in the reactor.

Some traditional continuous manufacturing sequences using traditionaldevices have been used to synthesize four APIs: diphenhydraminehydrochloride (BENADRYL®), lidocaine hydrochloride, diazepam (VALIUM®),and fluoxetine hydrochloride. (See, e.g., Adamo, A. et al., On-demandcontinuous-flow production of pharmaceuticals in a compact,reconfigurable system, Science, vol. 352, 6281, 61-67 (2016)). The unitoperation and unit process steps/devices repeatedly used in suchtraditional continuous manufacturing sequences are: a reactor, apacked-bed column-based solvent extractor, a gravity-based liquid-liquidseparator, a filter, a reagent/solvent delivery and mixing, a heater, acharcoal cartridge for adsorption, a precipitation/crystallizationdevice, and an occasional membrane separator. See id.

FIG. 2 is a flowchart showing the upstream and downstream synthesis ofdiphenhydramine hydrochloride (BENADRYL®) using a traditionalreconfigurable system 30. (See, e.g., Adamo, A. et al., On-demandcontinuous-flow production of pharmaceuticals in a compact,reconfigurable system, Science, vol. 352, 6281, 61-67 (2016)). Thecomponents of the system 30 include a 10 mL reactor 32, a back-pressureregulator 34, a heater 36, a packed-bed column 38, a gravity-basedseparator 40, a charcoal cartridge 44, and a Fourier Transform InfraredSpectroscopy instrument 46 (FlowIR). After addition of HCl, the APIprecipitates and is filtered (filter not shown in FIG. 2 ).

FIG. 3A is a flowchart showing the synthesis of lidocaine hydrochlorideusing a two-step upstream system 50 configuration. (See, e.g., Adamo, A.et al., On-demand continuous-flow production of pharmaceuticals in acompact, reconfigurable system, Science, vol. 352, 6281, 61-67 (2016)).The system 50 includes a 10 mL reactor 52, a 30 mL reactor 54, aback-pressure regulator 56, a packed-bed column-based solvent extractor58, a gravity-based separator 60, and a FlowIR 64.

FIG. 3B is a flowchart showing the synthesis of diazepam (VALIUM®) usinga two-step upstream system 70 configuration. The system 70 includes two10 mL reactors 72, 74, a back-pressure regulator 76, a packed-bed column78, gravity-based separators 80, 86, a charcoal cartridge 82, and aFlowIR 84.

As shown from FIGS. 1, 2 and 3A-3B, there is currently an interest inmanufacturing APIs using a continuous manufacturing process. However,traditional continuous production processes may result in lowefficiency, operational problems, reduced or lack of control overproduction, combinations thereof, or the like. Accordingly, there is aneed for an improved continuous process for production of APIs.

SUMMARY

The present invention relates to a method to continuously produce APIsincluding the use of membrane-based devices. In some embodiments,membrane-based devices can be incorporated at one or more steps of theAPI manufacturing process. In some embodiments, membrane-based devicescan be incorporated at every step of the API manufacturing process. Themolecular weights of the APIs can be in the range of, e.g., 150-1100 Dainclusive, 150-1000 Da inclusive, 150-900 Da inclusive, 150-800 Dainclusive, 150-700 Da inclusive, 150-600 Da inclusive, 150-500 Dainclusive, 150-400 Da inclusive, 150-300 Da inclusive, 150-200 Dainclusive, 200-1100 Da inclusive, 300-1100 Da inclusive, 400-1100 Dainclusive, 500-1100 Da inclusive, 600-1100 Da inclusive, 700-1100 Dainclusive, 800-1100 Da inclusive, 900-1100 Da inclusive, 1000-1100 Dainclusive, 200-1000 Da inclusive, 300-900 Da inclusive, 400-800 Dainclusive, 500-700 Da inclusive, 150 Da, 200 Da, 300 Da, 400 Da, 500 Da,600 Da, 700 Da, 800 Da, 900 Da, 1000 Da, 1100 Da, or the like. In someembodiments, other molecular weights can be used.

In some embodiments, the exemplary method to produce APIs can includeseveral steps. Initially, a reaction mixture with an API precursor issubjected to solvent extraction to produce a reactant stream with theAPI precursor. The API precursor is concentrated in the reactant streamusing at least one membrane. The API precursor undergoes conversion inthe reactor and is then separated from the reaction mixture stream usinga separator. The converted API precursor is then crystallized using acrystallizer to produce APIs. Before and after the reaction step, theAPI precursor and the converted API precursor in solution may undergoheating or cooling.

The exemplary method incorporates membrane devices and processes. Incontrast to traditional methods, such as batch manufacturing andcontinuous processes using non-membrane devices and processes, membranetechnologies are compact, modular, scalable, and highly energyefficient. Membrane technologies are also capable of many separations ina continuous fashion. Membrane reactors can reach a higher level ofsynthesis than the tubular reactors traditionally used for APIproduction. Generally, flow chemistry-based approaches use simplechannel/tubular flows and can encounter severe additional challengeswith multiphasic systems (gas-liquid, liquid-liquid, solid-liquid, orsolid-liquid-gas). Membrane crystallizers, membrane mixers, and solidhollow fiber and ceramic tubular exchangers can carry out the process ofcrystallization, mixing, and/or heat exchange, respectively, much moreefficiently than conventional non-membrane based devices.

In some embodiments, every unit (or virtually every unit) used in APImanufacturing can be a membrane device. In such embodiments, all unitscan be connected in a serial fashion and operate continuously to enablecontinuous membrane-based production of APIs (without batch processing).

In general, a central component of an API production system includesreactors for synthesis of pharmaceutical intermediates and the API. APIsynthesis can involve a number of reaction steps, e.g., from 2, 3, 4 to20 reaction steps, or more. In the exemplary method, each reaction stepcan be carried out in a membrane reactor in a continuous fashion. Stepsrelated to any reaction carried out before introduction to the reactor(such as mixing reactants, heating the feed, or the like) or after thereaction (such as quenching the post-reaction mixture or cooling) can becarried out using membrane-based devices. In some embodiments, themembrane reactor itself can carry out additional functions, such as feedmixture separation or product mixture separation.

In some embodiments, after each reaction, membrane separation steps canbe coupled with the membrane reactor output andseparations/purifications of the intermediates/API can be carried out.In some embodiments, membrane reactors can be used at every synthesisstep, with the membrane reactors supported by membrane separations ateach post-reaction processing step. All of the noted steps can becarried out continuously to continuously manufacture APIs.

In some aspects, the present invention relates to a method of producingactive pharmaceutical ingredients (APIs), including: (a) subjecting areaction mixture with an API precursor to solvent extraction to producea reactant stream with the API precursor; (b) concentrating the APIprecursor in the reactant stream using at least one membrane; (c)carrying out a reaction in a membrane reactor; (d) separating the APIprecursor from the reaction stream using a separator; and crystallizingthe API precursor using a crystallizer to produce APIs.

In some embodiments, at least one of a reactor for performing step (a),the separator of step (d), or the crystallizer of step (e) is amembrane-based device. In some embodiments, the method of producing APIsincludes heating, cooling, and/or quenching of solutions containingactive pharmaceutical ingredients using solid hollow fiber heatexchangers. In further embodiments, the heat exchangers aremembrane-based. In some embodiments, the method of producing APIsincludes removing impurities from organic process streams using membraneadsorbers.

In some aspects, the present invention relates to a method for solventexchange and nanofiltration or reverse osmosis, including: (a) adding asolvent to a reaction mixture; and (b) removing preexisting solvent fromthe reaction mixture through a membrane by organic solventnanofiltration or organic solvent reverse osmosis.

In some aspects, the present invention relates to a method to immobilizecatalysts in pores of polymeric or ceramic planar, tubular or hollowfiber membranes for carrying out two-phase based reactions in thismembrane reactor for gas-liquid systems as well as liquid-liquidsystems.

In some aspects, the present invention relates to a method to immobilizea catalyst using membrane-based devices in enzyme catalysis, including:(a) directing a reaction mixture containing small molecule substratesand products through a membrane reactor lined with chargednanofiltration membranes; and (b) segregating a catalyst and cofactor inthe reactor and immobilizing the catalyst in a membrane.

In some aspects, the present invention relates to a method forcontinuous manufacturing of prexasertib monolactate monohydrate, saidmethod including the steps of:

(a) combining compound 7 with hydrazine in the presence of acetic acidin methanol and THF at the temperature of about 130° C. to producecompound 8:

(b) combining compound 8 with compound 9 in the presence ofN-ethylmorpholine in DMSO at the temperature of about 85° C. to producecompound 10:

(c) deprotecting compound 10 by combining it with formic acid at thetemperature of about 25° to produce compound 1:

and(d) subjecting compound 1 to lactic acid distillation in THF/water toproduce compound 12:

wherein each of steps (a)-(d) is carried out in a series of unitsconnected to each other, e.g., using tubing, to support continuous flow;and wherein said series of units includes at least one membrane-basedunit.

In some embodiments, at least step (a) is carried out in amembrane-based unit. In some embodiments, at least step (b) is carriedout in a membrane-based unit. In some embodiments, at least step (c) iscarried out in a membrane-based unit. In some embodiments, at least step(d) is carried out in a membrane-based unit. In further embodiments,each of steps (a)-(d) is carried out in a membrane-based unit.

In some embodiments, where at least step (a) is carried out in amembrane-based unit, the membrane-based unit is a membrane-based reactorunit, e.g., a Pore Flow Through Reactor (PFTR). In some embodiments, themethod further includes, after step (a), combining compound 8 withtoluene and carrying out countercurrent solvent extraction using amembrane-based unit to yield compound 8 in a mixture of toluene,methanol, water and THF, wherein said membrane-based unit is apervaporation membrane device.

In some embodiments, in a countercurrent membrane solvent extraction ofcompound 8 from a substantial water-containing polar solution alsocontaining methanol and THF, toluene is passed in a countercurrentdirection on the other side of the porous membrane to extract compound 8along with some methanol and THF from the water phase (flowing in theopposite direction) which is generated by adding some water on the otherside of the membrane at the other end of the extractor.

In some embodiments, pervaporation (PV) process removes volatilesolvents, such as methanol, THF and toluene after addition of DMSOthrough a perfluoropolymer based PV membrane, prior to step (b). In someembodiments, membrane-based solvent extraction in a two-phase systemresults in an aqueous phase extracting the following impurities:hydrazine, acetic acid and deprotected compound 8. In some embodiments,the level of impurities achieved after extraction is hydrazine: <2 partsper million relative to the compound 8, and the deprotected compound 8reduced to less than 1% from as much as 5% in the solution prior toextraction.

In some embodiments, the method further includes adding DMSO to compound8 in toluene, methanol, water and THF to produce a mixture; andintroducing said mixture into a membrane-based unit to remove toluene,methanol and water from said mixture by pervaporation. In someembodiments, the removal of toluene, methanol and water from saidmixture by pervaporation is carried out at the temperature of about 60°C. In some embodiments, the membrane-based unit includes aperfluorocopolymer membrane.

In some embodiments, the method includes, prior to step (b), combiningcompound 8 with compound 9 in DMSO in a membrane-based unit to produce amixture of compound 8 and compound 9 in DMSO, wherein the membrane-basedunit is a membrane mixer. In some embodiments, the membrane mixer is aporous hollow membrane mixer. In a further embodiment, themembrane-based unit is a Pore Flow Through Reactor (PFTR). In someembodiments, when at least step (c) is carried out in a membrane-basedunit, the membrane-based unit is a Pore Flow Through Reactor (PFTR). Insome embodiments, when at least step (d) is carried out in amembrane-based unit, the membrane-based unit is a pervaporation membranedevice. In further embodiments, the pervaporation membrane deviceincludes a perfluorocopolymer membrane.

In some aspects, the present invention relates to a system forcontinuous manufacturing of prexasertib monolactate monohydrate inaccordance with the method of the invention, the system includes aseries of units connected to each other, e.g., using tubing, to supportcontinuous flow, wherein at least one unit in said system is amembrane-based unit. In some embodiments, the system is 500 asillustrated in FIG. 8 . In some aspects, the present invention relatesto a method for continuous manufacturing of fluoxetine hydrochloride,the method includes (a) reacting compound 13 with diisobutylaluminiumhydride (DIBALH) in water/hydrochloric acid at a temperature of about25° C. to produce compound 14:

(b) combining compound 14 with methylamine at a temperature of about135° C. to produce compound 15:

and(c) combining compound 15 with compound 16 in the presence of potassiumtert-butoxide and a crown ether at a temperature of about 140° C. toproduce compound 17:

wherein each of steps (a)-(c) is carried out in a series of unitsconnected to each other, e.g., using tubing, to support continuous flow;and wherein said series of units includes at least one membrane-basedunit.

In some embodiments, at least step (a) is carried out in amembrane-based unit. In some embodiments, at least step (b) is carriedout in a membrane-based unit. In some embodiments, at least step (c) iscarried out in a membrane-based unit. In some embodiments, each of steps(a)-(c) is carried out in a membrane-based unit. In some embodiments,when step (a) is carried out in a membrane-based unit, themembrane-based unit is a Pore Flow through Reactor (PFTR).

In some embodiments, the method further includes performing solventextraction-based removal of aluminum salts and other polar impuritiesinto aqueous phase to purify compound 14 present in toluene phase byintroducing a solution comprising compound 14 into a membrane-basedunit, wherein said membrane-based unit is a liquid-liquid (L-L)nondispersive membrane reactor

In some embodiments, the method further includes performing solventextraction after step (b) in a membrane-based unit to produce a mixtureof compound 15 in THF. In further embodiments, the membrane-based unitis a liquid-liquid nondispersive membrane solvent extraction unit (L-LMSX unit).

In some embodiments, the method further includes removing residual waterleft in the mixture of compound 15 in THF by passing said mixturethrough a membrane-based unit. In some embodiments, the membrane-basedunit is a pervaporation membrane device. In some embodiments, thepervaporation membrane device includes a perfluorocopolymer membrane. Insome embodiments, when step (c) is carried out in a membrane-based unit,the membrane-based unit is a Pore Flow through Reactor (PFTR).

In some embodiments, the method further includes, after step (c),extracting compound 17 with tert-butyl methyl ether (TBME) in amembrane-based unit. In some embodiments, the membrane-based unit is aliquid-liquid nondispersive membrane solvent extraction unit (L-L MSXunit). In some aspects, the present invention also relates to a systemfor continuous manufacturing of fluoxetine hydrochloride in accordancewith methods of the invention, the system including a series of unitsconnected to each other, e.g., using tubing, to support continuous flow,wherein at least one unit in said system is a membrane-based unit. Insome embodiments, the system is 600 as illustrated in FIG. 9 .

Any combination and/or permutation of these embodiments is envisioned.Other objects and features will become apparent from the followingdetailed description considered in conjunction with the accompanyingdrawings. It is to be understood, however, that the drawings aredesigned as an illustration only and not as a definition of the limitsof the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention, reference ismade to the following Detailed Description of the Invention, consideredin conjunction with the accompanying drawings, in which:

FIG. 1 is a schematic of a traditional continuous pharmaceuticalproduction sequence of reactors and separators followed by acrystallizer;

FIG. 2 is a flowchart showing the upstream and downstream synthesis ofdiphenhydramine hydrochloride (BENADRYL®) using a traditionalreconfigurable system;

FIG. 3A is a flowchart showing the synthesis of lidocaine hydrochlorideusing a traditional two-step upstream system configuration;

FIG. 3B is a flowchart showing the synthesis of diazepam (VALIUM®) usinga traditional two-step upstream system configuration;

FIG. 4 is a schematic of a multistep membrane-based API synthesis inaccordance with exemplary embodiments of the present disclosure;

FIG. 5 is a schematic of a dead end flow configuration of a porousceramic membrane disk-based reactor operating as a plug flow reactorcapable of being incorporated into the exemplary API synthesis system;

FIG. 6A is a schematic illustrating the synthetic route for a continuousmanufacturing production of prexasertib monolactate monohydrate asdescribed in Cole et al., Science 356, 1144-1150 (2017), the entirecontents of which are hereby incorporated herein by reference.

FIGS. 6B-6D are schematic illustrations of continuous manufacturing ofprexasertib monolactate monohydrate in accordance with the syntheticroute shown in FIG. 6A. Specifically, FIG. 6B is a schematicillustration of carrying out “Step 1” shown in FIG. 6A (Stage I). FIG.6C is a schematic illustration of carrying out “Step 2” and “Step 3”shown in FIG. 6A (Stage II). FIG. 6D is a schematic illustration ofcarrying out “Step 4” shown in FIG. 6A (Stage III)

FIG. 7 is a schematic illustration of synthesis system for continuousmanufacturing of fluoxetine hydrochloride (PROZAC®);

FIG. 8 is a schematic of membrane-facilitated continuous manufacturingoperation for Prexasertib Monolactate Monohydrate;

FIG. 9 is a schematic of continuous membrane-facilitated synthesis offluoxetine hydrochloride (PROZAC®); and

FIG. 10 is a schematic of a continuous membrane-facilitated syntheticroute for synthesis of fluoxetine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

As discussed herein, use of membrane-based API synthesis (as compared totraditional API synthesis) allows for considerable reduction of devicesused in the process. For example, traditional solvent extraction canfirst involve a mixer where one phase is dispersed as drops into anotherphase, then dispersed in a two phase system before being taken to asettler (often gravity based) to separate the two phases. This can beproblematic, besides requiring an additional device. In membrane-basedsolvent extraction, only one device is needed. In addition,membrane-based synthesis can be used to carry out an equilibrium-limitedreaction process and change the equilibrium conversion by removing oneof the products through the membrane and achieve a higher conversionand/or selectivity. (See, e.g., J. Whu et al., Modeling ofNanofiltration-assisted Organic Synthesis, J. Membrane Sci., 163(12),319-331 (1999); see also Park, B. G. et al., Design issues ofpervaporation membrane reactors for esterification, Chem. Eng. Sci., 57,4933 (2002)). Membrane-based synthesis allows for control of the feedintroduction rate, mixing of different reactants via a membrane into amembrane reactor, control of the reaction pathways, conversion, andselectivity. Membrane-based synthesis includes membrane devices that donot suffer from phase flow limitations encountered in conventionalseparation devices (which traditionally suffer from flooding and/orloading). Membrane-based devices can be scaled up or down easily,resulting in easier scale up or down of API manufacturing. Thus, using amembrane-based API synthesis system provides significant advantages overtraditional API manufacturing.

FIG. 4 is a schematic of a multistep membrane-based API synthesis system100 (hereinafter “system 100”) in accordance with exemplary embodimentsof the present disclosure. The system 100 can include a membrane-basedmixer 102, a first membrane reactor 104, a first heat exchanger 106(e.g., a hollow fiber heat exchanger), a first membrane-based solventseparator 108, a second membrane reactor 110, a second heat exchanger112 (e.g., a hollow fiber heat exchanger), a second membrane-basedsolvent separator 114, and a membrane-based crystallizer 116. The system100 therefore incorporates several membrane-based devices into thesequential steps of the process performed by the system 100. The systemcan incorporate all membrane-based devices to replace traditionalnon-membrane-based devices for the reaction processes and separationsteps, which can reduce the total number of devices used overall.

In some embodiments, the mixer 102 can be a porous hollow fiber membranemixer (such as the mixer FIG. 3A) instead of an inline mixer to mix neatchloroacetyl chloride (12) with N-methyl-2-pyrrolidone (NMP) and thenmix it with 2,6-xylidine (11) in N-methyl-2-pyrrolidone (NMP). In someembodiments, the membrane-based mixer 102 using porous membranes canitself be the subsequent membrane reactor 104 shown in FIG. 4 , therebyacting as both the mixer 102 and reactor 104. If the synthesis reactionis significantly exothermic and requires cooling during or after thereaction, a non-porous ceramic tubule or a non-porous polymeric hollowfiber based heat exchanger 106 can be used by the system 100 to cool thepost-reaction solution.

The cooled reaction product-containing solution undergoes membraneseparation in the membrane separator 108, which can be of one of severaltypes of separators. In some embodiments, if the solvent has to beexchanged with another solvent to prepare for the next synthesisreaction, the system 100 can use an organic solvent nanofiltration (OSN)with continuous addition of the replacement solvent to the flowing feedsolution and removal of the solvents (as shown by the arrows extendingout of the separator 108 in FIG. 4 ) without removing the intermediateproduct(s) formed in the reactor. Simultaneously, the concentration ofthe desired solvent increases in the feed solution to the membrane unit.In some embodiments, the system 100 can use a highly selective organicsolvent reverse osmosis (OSRO) membrane in the membrane separator 108 toremove the undesired solvent through the membrane while retaining thesolvent needed in the solvent exchange process. The reactionintermediate product is retained by the membrane.

In some embodiments, the system 100 can use nondispersive membranesolvent extraction (MSX) in the separator 108 to removeundesirables/impurities from the reaction product stream through aporous membrane into an extracting immiscible solvent. In someembodiments, the desired intermediate product in the solution exitingthe reactor 104 can be extracted into the extracting solvent through themembrane by MSX and taken to the next synthesis step of the process.Such membrane solvent extraction step combines two steps identified inFIGS. 3A and 3B as the packed-bed column and gravity-based separatorinto a single step/device without any dispersion of one phase into theother.

An example for such a step is provided in FIG. 2 where preheated aqueoussodium hydroxide (3M) is used to dissolve the reaction product (from thereactor), although the resulting solution contains some impurities. Inparticular, FIG. 2 shows the mixer 38 followed by a gravity-basedsettler 40. Extraction from one phase to the other phase in the mixer 38is achieved with high interfacial area via one phase present asdispersed drops in the other phase. Using a gravity-based phase settler40, the lighter phase goes up and the heavier phase goes down to thebottom, thus separating the two phases. Gravity-based phase separationis usually problematic, generally necessitating the use of a separatemembrane separator device for phase separation. (See, e.g., M. Peer etal., Biphasic catalytic hydrogen peroxide oxidation of alcohols in flow:Scale-up and extraction, Org. Process Res. Dev., 20, 1677-1685 (2016)).This can be highly problematic in flow chemistry where in biphasicsystems, one employs dispersive mode of operation which creates problemsduring phase coalescence. Instead of two such potentially problematicdevices, membrane solvent extraction uses only one device and does notdisperse one phase into the other. The phases contact each other at themembrane pore mouth without dispersion. Therefore, no gravity-basedseparator is needed. Extraction is far more efficient and the devicesize is an order of magnitude smaller without emulsion problems andconsequent API precursor loss. The resulting aqueous solution is nextsubjected to membrane solvent extraction with hexane, extracting thedesired reaction product, which later yields diphenhydraminehydrochloride after treatment with HCl.

As illustrated in FIG. 4 , the membrane-based mixer 102 receives a firstfluid (fluid 1) into the membrane channel, and simultaneously receives asecond fluid (fluid 2) on both sides of the membrane channel. The mixer102 includes a porous membrane (e.g., porous hollow fiber membrane)forming the walls of the membrane channel and defining the membranechannel relative to the surrounding channels for the second fluid.During the process, the second fluid is forced to pass through the poresof the membrane into the first fluid on the other side of the membrane.

Similarly, the reactor 104 includes a porous/microporous/dense membranethrough which the solution passes surrounded by outer channels intowhich the reactants are introduced, such that the reactants are forcedto pass through the pores of the membrane and into the solution. Theseparator 108 includes the inner sub-nanoporous membrane channel andsolvent is pushed through the pores of the membrane and out of theseparator 108. A similar process is repeated in the reactor 110, theheat exchanger 112, and the separator 114 (and can be repeated inadditional reactors, heat exchangers, and separators) before progressingto the membrane crystallizer 116. Two or more reactants are needed for areaction in reactor 104. These may come in through the solution.Alternatively, one or more reactants can come with the solution, andadditional reactants can be slowly introduced from the outside throughthe pores in the membrane wall into the reactor 104. This enablesachieving a controlled rate of reaction. A membrane separator can be ofvarious types. If a solvent from the reaction media is to be removed,pressure can be applied on the solution in the membrane separator andpass the solvent and not the intermediate product through ananofiltration membrane. Alternatively, if water has been produced inthe reaction and is present as an esterification reaction, by pulling avacuum on the other side of the membrane, water can be removed by apervaporation process selectively through a nanoporous membrane. Thisincreases the conversion of the process and allows one to obtain ahigher yield of the intermediate product. Each of the units is thesystem 100 used in continuous pharmaceutical/API manufacturing thereforeuses a corresponding membrane-base unit (as compared to non-membraneunits in traditional continuous API manufacturing systems). Essentiallyevery step in the continuous pharmaceutical/API synthesis processesdiscussed herein can be implemented continuously and efficiently usingmembrane technologies and membrane-based processes.

Membranes used by the system can be of various types depending on theneeds of the user and/or end product. A nonporous membrane can be used,but allows small molecules and/or solvents to go through (as in reverseosmosis process and pervaporation process) when pressure is applied tothe feed solution and/or vacuum is pulled on the other side. Thetransport corridors in the nonporous membrane can be slightly increasedin nanofiltration membranes to allow larger molecules of molecularweight of up to about 1,100 Dalton to not go through the membrane, whilesolvents pass through much faster. Membranes having larger transportcorridors appropriately termed pores can be used for a variety ofseparations, such as ultrafiltration. Membranes having these types ofsomewhat larger pores can be used for mixing, membrane solventextraction, or the like.

In some embodiments, only one device used in the continuouspharmaceutical/API manufacturing system 100 is replaced by acorresponding membrane-based unit. In instances where only one or twodevices in the system 100 are replaced by membrane-based units (e.g.,not all possible units are membrane-based), the API manufacturingprocess continues to be improved as compared to traditional synthesis,but may result in less conversion, less recovery, and potentially moreoperating problems (as compared to a fully membrane-based process). Forexample, the packed bed and the gravity separator used in conventionalcontinuous pharmaceutical/API manufacturing (e.g., FIGS. 2, 3A, and 3B)can be replaced by a membrane solvent extraction device. As anotherexample, consider a porous/microporous membrane. If it is hydrophobic,its pores are more likely to be wetted by the organic phase being usedin the solvent extraction and flowing on one side of the membrane. If anaqueous phase flows on the other side of the membrane at a pressureequal to or higher than that of the organic phase, then themembrane-wetting organic phase cannot appear on the other side of themembrane where the aqueous phase is flowing. However, the phaseinterface between the organic and aqueous phase is immobilized at themembrane pore mouth. Then, solvent extraction or back extraction cantake place across this aqueous-organic phase interface from the aqueousto the organic, or the organic to the aqueous phase, respectively. Aslong as the aqueous phase pressure does not exceed that of the organicphase by an amount exceeding a breakthrough pressure, theaqueous-organic phase interface remains immobilized and nondispersivesolvent extraction takes place. There is no need for a settler as ingravity-based separator/settler used in FIGS. 2, 3A and 3B.

Alternatively, various other dispersive solvent extraction devices ofthe system 100 (such as a mixer and/or a settler) can be replaced by amembrane solvent extraction (MSX) device. In some embodiments, onlycertain devices used in continuous pharmaceutical/API manufacturing canbe replaced by corresponding membrane-based units. In some embodiments,one group of components (e.g., mixer, reactor, heat exchanger andseparator) can be membrane-based, while a subsequent group of componentscan be non-membrane-based. However, at least two steps of the exemplaryprocess and system incorporate a membrane-based device and process.

In some membrane-based devices, referred to as membrane contactors, themembrane contactor device facilitates the conventionalreaction/separation step by bringing two immiscible phases into contactwithout any dispersion of one phase into the other phase. Becausedispersion is eliminated, coalescence of the phases is no longerrequired.

While phase contacting generally requires dispersion of one immisciblephase into another immiscible phase, a porous membrane contactor caneliminate dispersion and yet provides a contacting surface area betweenthe two phases that can be up to 5-20 times what is achieved in adispersion-based device. Membrane contactor-based devices can alsoprevent emulsion formation when contacting two immiscible liquid phases.However, if contacting requires creating an emulsion, porousmembrane-based devices can achieve such emulsion with a much highercontrol over the size of the emulsion droplets. In addition, themembrane contactors can bring two miscible phases into intimate contactand achieve mixing, thereby developing a membrane mixer (such as mixer102 of FIG. 4 ).

Catalytic or noncatalytic gas-liquid reactions, such as hydrogenation,aerobic oxidation, carboxylation using CO₂, and ozonation, can becarried out in a tubular and hollow fiber membrane contactor, and caneasily accommodate scale-up. Catalytic or noncatalytic liquid-liquidreactions requiring mixing of two miscible liquid phases can be carriedout with excellent mixing efficiency in a porous hollow fibermembrane-based device mixer, such as a membrane mixer 102, or a flatmembrane-based device. One of the streams to be mixed can be introducedin a distributed fashion through the membrane pores into the otherstream flowing on the other side of the membrane. This allows for anincreased level of control.

It will be understood that such membrane-based reaction devices can beshort or long to accommodate the needs of the reaction, residence timerequirement, combinations thereof, or the like. It will also beunderstood that several membrane-based reaction devices can be combinedin different methods/systems to accommodate the needs of the reaction.For example, short reactors can be followed by solid polymeric hollowfiber membrane-based heat exchangers, dense ceramic tubule-based heatexchangers, or conventional heat exchangers for exothermic reactions.Therefore, in some embodiments, a short reactor can be used followed bya heat exchanger, followed by another short reactor, followed by anotherheat exchanger, and so on until the desired conversion is attained.

After each synthesis step in a conventional pharmaceutical synthesis,the solvent may need to be exchanged and the catalysts may need to bereplaced before the next reaction step. Such work-up involves asignificant number of separation steps, including distillation, solventextraction, and adsorption, which complicates the synthesis process andcan have a negative effect on the resulting API. Using the system 100,such separation steps can be implemented at near room temperature usingporous membrane-based nondispersive membrane solvent extraction (MSX) ordense or relatively dense polymeric membranes through nanofiltration(OSN), reverse osmosis (OSRO), pervaporation, combinations thereof, orthe like. If a volatile solvent (including water) must be removed,membrane pervaporation can be implemented to selectively remove thevolatile solvent from the feed mixture through the membrane. If thesolvent must be removed and the intermediate compound must beconcentrated, organic solvent nanofiltration (OSN) can be used. Ifsolvent exchange must be implemented, OSN can be used in thediafiltration mode with the exchange solvent introduced. Alternately,after the exchange solvent is introduced, the system 100 can use organicsolvent reverse osmosis (OSRO) to remove the undesired solvent through asolvent-resistant reverse osmosis membrane at room temperature.

Conventional membrane operations are intrinsically continuous. Membranedevices are scalable, and can be scaled up or down. The membrane devicescan carry out the reaction-separation and associated steps in APIsynthesis in a continuous manner. The steps of an exemplary embodimentof the continuous production of APIs can include (1) membrane solventextraction; (2) reverse osmosis (RO) and nanofiltration (NF); (3)membrane pervaporation; (4) membrane mixing; (5) membrane reactors; (6)enzymatic synthesis; (7) hollow fiber heat exchangers; (8) membraneadsorption; and (9) membrane crystallization. Membrane fouling isconsidered after describing these membrane-based steps. Each of thesteps is described in greater detail herein.

In some embodiments, a membrane solvent extraction (MSX) device can beused. MSX devices can replace a packed-bed column-based solventextractor and a gravity settler, which are used in the processes shownin FIGS. 2 and 3A-3B. Hollow fiber (HF) microporous membrane-baseddevices can be used for non-dispersive solvent extraction (NDSX), whichremoves the need for a gravity-based separator. (See, e.g., Sirkar, K.K. Membranes, phase interfaces and separations: Novel techniques andmembranes—An overview, I&EC Res., 47, 5250-5266 (2008)). MSX devices aresignificantly smaller than dispersion-based devices, and they do notsuffer flooding or loading issues. Additionally, MSX devices can havealmost any flow rate ratio between the two immiscible phases flowing ontwo sides of the membrane. Wider commercialization of such devices hasnot been achieved due to non-availability of membranes that areresistant to many pharmaceutically relevant solvents. At present,polytetrafluoroethylene (PTFE)-based microporous membranes havingsmaller pore sizes are in the marketplace and can be used by the system100. (See, e.g., Singh, D. et al., High temperature direct contactmembrane distillation-based desalination using PTFE hollow fibers, Chem.Eng. Sci., 116, 824-833 (2014)). Reduction of the membrane pore size vianovel strategies would allow extraordinary flexibility in NDSX operationand application.

Following synthesis, solvent exchange is generally needed. Solventexchange is generally carried out by distillation, either vacuum-basedor otherwise. In some embodiments, the exchange can be conductedathermally because pharmaceutical intermediates and APIs are thermallysensitive. In some embodiments, the next solvent can be added to the mixand then the previous solvent is taken out through an appropriatemembrane by organic solvent reverse osmosis (OSRO) at about 25° C.Recent results have shown that with a particular perfluoropolymermembrane, pure toluene can be obtained as permeate from its binarymixtures with polar aprotic solvents, such as NMP, DMSO, and DMF, atpressures around 3,500-4,000 kPa. (See, e.g., Chau, J. et al., Reverseosmosis separation of particular organic solvent mixtures by aperfluorodioxole copolymer membrane, J. Membrane Sci., 563, 541-551(2018)). Pressures used in commercialized RO desalination are often muchhigher. Research has shown that pure methanol is obtained as permeatefrom its binary mixtures with polar aprotics, e.g., NMP. See id.Further, recent MD simulations of organic solvent nanofiltration (OSN)membranes have proven to be inadequate, as these membranes have noselectivity for organic solvent mixtures (OSMs). (See, e.g., Liu, J. etal., A molecular simulation protocol for swelling and organic solventnanofiltration of polymer membranes, J. Membrane Sci., 573, 639-646(2019)).

Concentration of the APIs in the solvent can be achieved by usingorganic solvent nanofiltration (OSN) membranes enabling athermal removalof one or more solvents or an exchange with another solvent for APIsduring API synthesis. (See, e.g., Marchetti P. et al., Molecularseparation with organic solvent nanofiltration: A critical review, Chem.Rev. 114, 10735-10806 (2014); Sheth, J. et al., Nanofiltration-baseddiafiltration process for solvent exchange in pharmaceuticalmanufacturing, J. Membrane Sci., 211(2), 251-261 (2003)). Membranes forsuch steps are demanding for polar aprotic solvents and thereforerequire significant research. Production of numerous OSMs is ubiquitousin API synthesis. Thus, advanced membranes for pressure-driven OSN andOSRO processes can allow athermal operation and simultaneously achievesignificant energy efficiency. OSN membranes that reject Jacobsencatalyst (622 Da), Wilkinson catalyst (925 Da), and Pd-BINAP (849 Da)can be used to remove the intermediate product and the solvent whileholding back the larger size catalyst. (See, e.g., Scarpello, J. T. etal., The separation of homogeneous organometallic catalysts usingsolvent resistant nanofiltration, J. Membrane Sci. 203:71-85 (2002);Wong, H. T. et al., Recovery and reuse of ionic liquids and palladiumcatalyst for Suzuki reactions using organic solvent nanofiltration.Green Chem., 8, 373-399 (2006); Luthra, S. S. et al., Homogeneous phasetransfer catalyst recovery and re-use using solvent resistant membranes.J. Membrane Sci., 201:65-75 (2002)).

Membrane pervaporation can be used by the system 100 during synthesis toremove unneeded solvents, such as water and volatile solvents, from thesolution containing the API or other pharmaceutical intermediate. Thepervaporation device can be incorporated into one or both of themembrane-based separator 108, 114 of FIG. 4 . The pervaporation membraneallows volatile solvent to be removed through the membrane from themedium obtained after the reaction is completed. A typical volatilesolvent removed is water. The pervaporation membrane can also beincorporated into and implemented in the reactor itself. The membranepervaporation device can include dense membranes and a vacuum. In oneembodiment, membrane pervaporation can be conducted at about roomtemperature. Continuous production of anhydrous tert-butyl hydroperoxidein nonane is one example of this process. (See, e.g., Li, B. et al.,Continuous production of anhydrous tert-butyl hydroperoxide in nonaneusing membrane pervaporation and its application in flow oxidation of aγ-butyrolactam, Org. Process Res. Dev., 22, 707-720 (2018)).

To transition from batch processing in stirred tank reactors tocontinuous reactions, static mixer-aided tubular metallic reactors aswell as microreactors are being studied extensively. (See, e.g.,LaPorte, T. L. et al., Process development and case studies ofcontinuous reactor systems for production of API and pharmaceuticalintermediates, Chap. 23, pages 437-455, in Am Ende, D. (Ed.), “ChemicalEngineering in the Pharmaceutical Industry: R&D to Manufacturing”, JohnWiley & Sons, Hoboken, NJ (2011)). Mixing various reactants is anintegral step before such liquid-liquid reactions. In some embodiments,thermally and chemically inert porous hollow fiber membranes (HFMs) andceramic tubular membranes can be used by the system 100 to achieveextraordinary mixing of two liquid phase reactant streams flowing on twosides of the membrane and can carry out synthesis under controlledconditions. The use of a porous HFM to achieve high mixing efficiency oftwo liquid streams on one side of the membrane has been shown withmiscible aqueous and selected organic phases under room temperatureconditions. (See, e.g., Chen, D. et al., Hydrodynamic modeling of poroushollow fiber anti-solvent crystallizer for continuous production of drugcrystals, J. Membrane Sci., 556, 185-195 (2018a); Fern, J. C. W. et al.,Continuous synthesis of nano-drug particles by antisolventcrystallization using a porous hollow-fiber membrane module, Int. J.Pharmaceut, 543, 139-150 (2018); Zarkadas, D. M. et al., Antisolventcrystallization in porous hollow fiber devices, Chem. Eng. Sci., 61(15),5030-5048 (2006)).

Membrane emulsification can be used to mix immiscible phases requiringan emulsion-containing feed phase in a membrane reactor. (See, e.g.,Joscelyne, S. M. et al., Membrane emulsification: a literature review.J. Membrane Sci. 2000, 169, 107-117). The immiscible phase is forcedthrough the membrane pores into the reaction media on the other side ofthe membrane. Such membrane emulsification can be incorporated into themixer 102.

The membrane reactor 104 can be used to/for, e.g., separate productsfrom the reaction mixture, separate a reactant from a mixed stream forintroduction into the reactor, control addition of one reactant or tworeactants to the stream, nondispersive phase contacting with reaction atthe phase interface or in the bulk phases, segregation of a catalyst andcofactor in a reactor, immobilization of a catalyst in or on a membrane,combinations thereof or the like. In some embodiments, the membrane canbe the catalyst and/or the reactor. In some embodiments, the mixingdevice (e.g., mixer 102) can be the reactor 104 itself.

For miscible liquid phase-based reactions and gas-liquid reactions, suchas hydrogenation, in pharmaceutical synthesis, porous tubular ceramicand porous HFM-based devices can simultaneously immobilize catalysts,achieve high mixing efficiency and controlled synthesis. Membrane-basedozonation has previously been used for water treatment. (See, e.g.,Shanbhag, P. V. et al., Membrane-based ozonation of organic compounds,I&EC Res., 37(11), 4388-4398 (1998)). Membrane reactors are useful forpharmaceutical synthesis using simple hollow fiber, membrane modules ofinert polymers, e.g., PTFE and ceramic membranes having hydrophobizedsurfaces.

Enzymatic catalysis can be used by the system 100 duringenantioselective synthesis in API production. A multiphase/extractivehollow fiber membrane bioreactor has been used for enzymatic resolutionof a diltiazem precursor, a poorly aqueous soluble ester, which washydrolyzed to an alcohol via an immobilized lipase and extracted by MSXinto an aqueous stream. (See, e.g., Lopez, J. L. et al., Amulti-phase/extractive enzyme membrane reactor for production ofdiltiazem chiral intermediate, J. Membrane Sci. 1997, 125, 189-211). Ina recent study involving synthesis of β-lactams that had undergonesite-selective C—H amidation using cytochrome P450 enzymes obtained bydirected evolution, it would have been useful to employ a membranereactor (similar to the reactor of the exemplary system 100) retainingthe enzyme. (See, e.g., Cho, I. et al., Site-selective enzymatic C—Hamidation for synthesis of diverse lactams, Science, 364 (6440), 575-578(2019)). In a membrane reactor lined with charged nanofiltration (NF)membranes for aqueous solutions, smaller molecule substrates andproducts flow through the NF membrane, while the enzyme and coenzyme arecontained within the enzyme reactor. (See, e.g., Nidetzky, B. et al.,Continuous enzymatic production of xylitol with simultaneous coenzymeregeneration in a charged membrane reactor. Biotechnol. Bioeng. 1996,52, 387-396). Site-directed mutagenesis and membrane pores and surfacescan be used to enhance enzyme life by immobilization.

Hollow fiber heat exchangers used by the system 100 allow for heating,cooling, and/or quenching of API-containing solutions. In someembodiments, the hollow fiber heat exchanger can be made of inert denseceramic/polymeric material. However, other suitable materials can beused for the heat exchanger. Polymeric hollow fiber heat exchangers(PHFHEs) demonstrated conductance/volume ratios 3-10 times higher thanshell-and-tube devices accompanied by low-pressure drops, reaching aslow as 1 kPa/NTU for lower temperature applications. (See, e.g.,Zarkadas, D. et al., Polymeric hollow fiber heat exchangers (PHFHEs): Analternative for lower temperature applications, I & EC Res., 43,8093-8106 (2004a); Song, L. et al., Polymeric hollow fiber heatexchangers for thermal desalination processes, I&EC Res., 49,11961-11977 (2010)). Thermally stable solvent-impermeable solid hollowfiber membranes, such as PTFE, can provide efficient heat-exchange wherefouling-based thermal resistance is of limited effect. Dense ceramicmembrane tubules can achieve heat exchange over much highertemperatures.

Membrane-based adsorbers can be used by the system 100 to exploitconvective flow through membrane pores. The membrane-based adsorbers canbe incorporated into one or both of the separators 108, 114 of FIG. 4 .For example, the adsorbers can be used to remove trace levels ofhomogeneous catalysts and allow for their recovery and reuse.Membrane-based adsorbers can be used to remove impurities from organicprocess streams during pharmaceutical synthesis. Membrane-basedadsorption processes have been adopted to produce biopharmaceuticals,either for adsorptive purification of monoclonal antibodies (mAbs) oradsorptive removal of impurities from the mAb-containingsolution/suspension. The technique is advantageous in its maximumutilization of the available sorption capacity and the rapidity withwhich it takes place. However, such traditional techniques have not beenused with a continuous process and need additional columns forcontinuous operation.

Membrane crystallization performed by the crystallizer 116 of the system100 is an essential step in API production as the production of dosageform kicks in. Membrane crystallization straddles two branches ofpharmaceutical manufacturing. Crystallization can be implementedcontinuously using HFMs at around room temperature and pressureconditions using anti-solvent crystallization or coolingcrystallization. Porous HFMs can be used to continuously crystallizeAPIs using anti-solvent crystallization, which allows for continuousnanocrystal production (if needed). Polymeric solid HFMs impermeable tothe solvents can be used to achieve continuous cooling crystallizationas PHFHE. Scale-up to increase the production rate in such membranedevices can be implemented with either an increase in the number ofhollow fibers in a larger shell or having a few units in parallel, sincemembrane devices are modular.

Membrane fouling can occur during API production as the fluid phase canbe complex with substances including dispersed particles, precipitates,and emulsions. Membrane fouling and its mitigation in pressure-drivenmembrane systems is consistently discussed in the industry. Membranefouling of this type is much less present in membrane contactor-basedoperations. Reducing membrane fouling in the system 100 allows forenhanced success of membrane-based approaches for multi-step APIsynthesis. Recent cross-flow hollow fiber membrane-based desalinationstudies on concentrating seawater to the level of 18-19% salt wasachieved without any flux reduction despite the scaling saltprecipitates of CaCO₃ and CaSO₄ floating around. (See, e.g., Song, L. etal., Pilot plant studies of novel membranes and devices for directcontact membrane distillation-based desalination, J. Membrane Sci., 323,257-270 (2008); Li, L. et al., Desalination performances of large hollowfiber-based DCMD devices, I&EC Res., 56, 1594-1603 (2017); Singh, D. etal., Novel cylindrical cross-flow hollow fiber membrane module fordirect contact membrane distillation-based desalination, J. MembraneSci., 545, 312-322 (2018)).

In some embodiments, reactor configurations using a membrane device canbe used. For example, the system 100 can include a 91 m long plug-flowreactor using a 4.57-mm-ID stainless steel tubing to condense a nitrilecompound with an excess of hydrazine at 130° C., 500 psig; with theresidence time in the reactor of 1 hr. (See, e.g., Cole, K. P. et al.,Kilogram-scale prexasertib monolactate monohydrate synthesis undercontinuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)).Such single-phase reaction can be carried out in a membrane poreoperating as if a plug flow reactor is provided with each pore.

In some embodiments, a porous alumina membrane disk can be used for areactor of the system 100. However, it will be understood that otherreactors can be used. FIG. 5 shows a schematic of a dead end flowconfiguration of a porous ceramic membrane disk-based reactor 200operating as a plug flow reactor. The reactor 200 can be incorporatedinto the system 100 as one of the reactors used in the API manufacturingprocess. The reactor 200 can include a disk body 202 with multiple pores204 extending through the body 202. The body 202 can itself form aporous membrane capable of permitting passage of liquid through thepores of the body 202. The pores 204 extend from one side to theopposing side of the body 202 to allow passage of the feed mixturetherethrough. The reactor 200 is referred to herein as a pore flowthrough reactor (PFTR). In the porous alumina (Al₂O₃) membrane disk ofFIG. 5 , each pore 204 acts as a separate plug flow reactor. The system100 can be used to deposit metallic or oxide catalysts on the pore 204wall surface for catalytic reactions. The pore L/D ratio in the ceramicdisk can be as high as 10³-10⁴ or even higher to provide the L/D ratioused in the stainless steel/PFA tubing. (See, e.g., Cole, K. P. et al.,Kilogram-scale prexasertib monolactate monohydrate synthesis undercontinuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)).Such a reactor can have an additional advantage in case the feed hassuspended material having dimensions larger than the pore 204 dimensions(discussed in the following paragraph below)

In some embodiments, to accommodate larger flow rates or longer reactorlengths, a ceramic monolith can be used for the reactor. In someembodiments, the reactor of the system 100 can be in the form of a stackof porous ceramic disks of small length and larger cross-sectional area,allowing the disks to function as a plug flow reactor. In someembodiments, the bulk feed mixture can flow tangentially over theceramic membrane disk in a recirculation mode as if the membrane were across-flow filter for a system containing particulate material, whichwould be rejected by the small size membrane pores. The reactor can bejacketed in an appropriate environment to maintain the thermalconditions needed in an appropriate pressure environment.

After each reaction, membrane separation steps can be coupled with themembrane reactor output and separations/purifications of theintermediates/API can be carried out by the system 100. Having themembrane reactors at each synthesis step can significantly enhancereactions in a multistep API synthesis and production process, with thereactors further supported by membrane separations at each post-reactionprocessing step. When a membrane reactor improves the selectivity orincreases the conversion, the amount of API manufactured is increased.Correspondingly, the load on the separation step(s) downstream of everymembrane reactor is decreased as the purification demands are reduced.Thus, use of membrane-based reactors at the synthesis steps providessignificant advantages to the final API manufactured in terms ofquantity and quality. All of these steps can be carried out continuouslyto continuously manufacture APIs.

Example of a Membrane-Based Manufacturing of APIs

A dead-end flow configuration of a porous ceramic membrane disk-basedreactor operating as a plug flow reactor is shown in FIG. 5 . Thismembrane can replace the 91 m long plug-flow reactor (as previously usedin Cole, K. P. et al., Kilogram-scale prexasertib monolactatemonohydrate synthesis under continuous-flow CGMP conditions, Science,356, 6281, 1144-1150 (2017)) by using a 4.57-mm-ID stainless steeltubing for condensation of a nitrile compound 7 with an excess ofhydrazine at 130° C., 500 psig to produce the compound 8 needed duringthe synthesis of prexasertib monolactate monohydrate. This is shown ingreater detail in FIG. 6B and discussed below.

FIG. 6B is a schematic illustrating the synthetic route for continuousmanufacturing of Stage I synthesis process 300 capable of beingperformed by the exemplary system. (See, e.g., Cole, K. P. et al.,Kilogram-scale prexasertib monolactate monohydrate synthesis undercontinuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)).In comparison, the exemplary system provided in FIG. 8 illustrates thesimpler and smaller implementation of membrane-based synthesis. Stillwith reference to FIG. 6B, Stage I begins as input 302 at step 1 to thecondensation PFR section 304, which progresses to the counter currentextraction section 306, and finally enters the rotary evaporatorconcentration section 308. The product is initially cooled down in adense ceramic tubular membrane heat exchanger or PTFE hollow fiber heatexchanger as it heats up the feed going into the PFR discussedpreviously. After cooling the product in a PTFE hollow fiber heatexchanger or a dense ceramic tubular membrane heat exchanger, toluene isadded to the organic stream containing compound 8 for countercurrentsolvent extraction while water is added from the other end of the mixersettler countercurrent extraction cascade (shown in FIG. 6B). A singleporous hollow fiber membrane solvent extraction device can be used inthe system of FIG. 8 to carry out continuous countercurrent extractionefficiently (instead of using a 6-device 3-stage extraction implementedtraditionally (as shown in FIG. 6B), which resulted in additionalproduct losses). See id. The residence time in the reactor is 1 hour.This single-phase reaction can be carried out in a dead-end flowconfiguration of a porous ceramic membrane disk-based reactor operatingas a plug flow reactor (see, e.g., reactor of FIG. 5 ). Rather thanusing a gas mixture (See, e.g., Motamedhashemi, Y. et al., Flow-throughcatalytic membrane reactors for the destruction of a chemical warfaresimulant: Dynamic performance aspects, Catalysis Today, 268,130-141(2016)), a liquid mixture is used.

The solvent extraction process discussed herein includes three stages(shown in FIGS. 6B and 6C), each with a mixing tank for rapid masstransfer between layers and a static gravity decanter for layerseparation, and provide the required purification with minimal productloss. Hydrazine is controlled to <2 parts per million (relative to 8traditionally), and the deprotected impurity can be removed from as muchas 5% traditionally to less than 1% of the total integrated productdistribution detected by high-performance liquid chromatography (HPLCarea %) after extraction.

Traditionally, DMSO was added to the product in a solution containingtoluene, methanol, water and THF after membrane solvent extraction.Next, a rotary evaporator concentration method is used to remove thevolatile solvents to yield a solution of 8 in DMSO (as shown in FIG.6B). See id. In some embodiments, this process can be performedcontinuously using a perfluoropolymer CMS-3 based pervaporationmembrane, which is highly selective in removing these solvents byemploying a vacuum on the permeate side of the membrane and has very lowpermeation of DMSO vis-à-vis the other solvents. (See, e.g., J. Tang etal., Permeation and Sorption of Organic Solvents and Separation of theirMixtures through Amorphous Perfluoropolymer Membrane in Pervaporation,J. Membrane Sci., 447, 345-354 (2013); J. Tang et al., PerfluoropolymerMembrane behaves like a Zeolite Membrane in Dehydration of AproticSolvents, J. Membrane Sci., 421-422, 211-216 (2012)). This would providea convenient membrane process where the CMS-3 membrane is completelyinert and has extremely low permeation of DMSO. (See, e.g., J. Tang etal., Perfluoropolymer Membrane behaves like a Zeolite Membrane inDehydration of Aprotic Solvents, J. Membrane Sci., 421-422, 211-216(2012)).

FIG. 6C shows a schematic of Stage II of the synthesis process 300.(See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactatemonohydrate synthesis under continuous-flow CGMP conditions, Science,356, 6281, 1144-1150 (2017)). Stage II includes an input 310 as step 2,an S_(N)Ar PFR section 312, an antisolvent crystallization MSMPR section314, a filtration/dissolution section 316, and a deprotection reactionsection 318. In Stage II, a solution of 8 in DMSO is mixed efficientlywith a solution of pyrazine type compound 9 (N-ethyl morpholine) in DMSOin a porous hollow fiber membrane mixer before introduction into aceramic membrane reactor of the type shown in FIG. 5 and maintained at85° C. This allows a long residence time needed for the S_(N)Ar typereaction between 8 and 9 to yield the pyrazole type compound 10. Toremove residual 9, the pyrazole-arylated regioisomers, low levels ofother process impurities, NEM·HCl, and DMSO, an anti-solventcrystallization (FIG. 6B) can be implemented easily with methanol usingthe technique of porous hollow fiber anti-solvent crystallization(instead of using a mixed suspension mixed product removal (MSMPR)crystallizer as shown in FIG. 6C). (See, e.g., Chen, D. et al.,Continuous synthesis of polymer-coated drug particles by a porous hollowfiber membrane-based antisolvent crystallization, Langmuir, 31, 432-441(2015)). Membrane-based devices can replace every single conventionaldevice used in synthesis of organic compounds to produce APIs inpharmaceutical industry. The process shown in FIGS. 6B-6C can thereforeincorporate membrane-based devices for each of the devices used, leadingto the compound 1 in FIG. 6C.

Next filtration and dissolution of 10 in formic acid (obtained afterfiltration and dissolution) and deprotection reaction is carried out ina reactor shown in FIG. 5 to end up with product 1 in formic acid. Thereactor used is similar to that in FIG. 5 , with the flow ratecontrolled to a very low rate to provide the needed liquid residencetime of around 4 hours and an appropriate length of the membranereactor. However, it can be useful to have a vertically upwardconfiguration of the reactor such that any gasses evolving can naturallytravel out through the top.

FIG. 6D is a schematic of Stage III synthesis process 300 of the system.(See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactatemonohydrate synthesis under continuous-flow CGMP conditions, Science,356, 6281, 1144-1150 (2017)). Stage III includes an input 320 at step 4,a rotary evaporator concentration section 322, a crystallization section324, and a filtration section 326.

FIGS. 6B-6D illustrate how a traditional continuous manufacturingprocess of specific APIs can be modified such that API synthesis isperformed using membrane-based devices and processes to replaceconventional non-membrane devices and processes for synthesis of aparticular API. In some embodiments, in Stage III illustrated in FIG.6D, first the four solutions (i.e., 1 in formic acid, lactic acid, waterand THF/water) may be mixed together in a porous hollow fiber membranemixer and then introduced into a membrane evaporator-concentrator (apervaporation membrane device) containing a perfluorocopolymer membraneto remove THF, water and formic acid with lactic acid remaining. Thelactic acid salt is then crystallized using THF as an anti-solvent in aporous hollow fiber antisolvent crystallizer mentioned earlier. Here,replacement of a filtration device (last device in FIG. 6D) by amembrane device is not necessary since a filter is a membrane device.

Another example of manufacturing a specific API using the exemplarysystem is the continuous manufacturing-based synthesis of fluoxetinehydrochloride (PROZAC®). (See, e.g., Adamo, A. et al., On-demandcontinuous-flow production of pharmaceuticals in a compact,reconfigurable system, Science, 352, 6281, 61-67 (2016), the entirecontents of which are hereby incorporated herein by reference). FIG. 7is a schematic of synthesis of the system 400 for continuousmanufacturing of fluoxetine hydrochloride (PROZAC®). The system 400includes an upstream section 402 and a downstream section 404. Theupstream section 402 includes reactors 406, 408, 410, 412,membrane-based separators 414, 416, 418, back pressure regulators 420,422, 424, 426, gravity based separator 428, heater 430, and MS cartridge432. FIG. 7 therefore shows a flowchart detailing the upstream anddownstream synthesis of fluoxetine hydrochloride.

In some embodiments, the first reactor 406 can be a membrane-basedreactor, which is used to carry out diisobutylaluminum hydride (DIBAL)reduction of 3-Chloropropiophenone in toluene using a PFTR. In furtherembodiments, the membrane-based reactor may be the reactor of FIG. 5 .

In some embodiments, the second reactor 408 may be a membrane-basedreactor, e.g., a liquid-liquid (L-L) nondispersive membrane reactor(MR). A solution of 4M HCl can be added into a membrane reactor 408,e.g., a liquid-liquid (L-L) nondispersive membrane reactor (MR). Theexiting stream from reactor 406 is introduced into the other side of theMR removing the need for a membrane separator. The aqueous stream goesto waste at the end of this reactor. Here, the L-L membrane reactor actsas a nondispersive membrane solvent extraction (MSX) device, which isused for solvent extraction in the membrane-based operations of thepresent disclosure, replacing traditional chemical engineering devices.The organic stream passes into an MSX device where 4M HCl stream isintroduced into the aqueous side. The aqueous stream is withdrawn towaste at the end of this device as shown in FIG. 7 .

In some embodiments, the third reactor 410 may be a membrane-basedreactor, e.g., a L-L nondispersive extractor/reactor. When twoimmiscible liquid phases exist in an L-L reactor, there will beextraction occurring from one phase to the other phase. To the organicstream containing the intermediate alcohol entering the reactor 410(Reactor III operating at 135° C.) which is a L-L nondispersiveextractor/reactor, an aqueous methylamine solution is introduced to theaqueous side.

In some embodiments, the system 400 may include an additionalmembrane-based device, e.g., a L-L nondispersive membrane solventextraction (MSX) device. The two immiscible product streams exitingreactor 410 can enter the additional membrane-based device, e.g., L-Lnondispersive membrane solvent extraction (MSX) device, into which twostreams are added: an aqueous 20% NaCl solution, and pure THF. Thesystem 400 allows amino alcohol to go into a suitable organic solvent(THF) for further reaction downstream in Reactor IV (reactor 412).Before that reaction in reactor 412, the aqueous phase is taken out fromthe aqueous stream at the end of the MSX device and sent to waste. Thewater left in the organic phase stream is removed by passing the organicstream through a membrane pervaporation device using perfluoropolymermembrane discussed herein instead of sending it through a bed ofzeolites (FIG. 7 ) (which is not a continuous process). (See, e.g., J.Tang et al., Perfluoropolymer membrane behaves like a zeolite membranein dehydration of aprotic solvents, J. Membrane Sci., 421-422, 211-216(2012); see also J. Tang et al., Permeation and sorption of organicsolvents and separation of their mixtures through amorphousperfluoropolymer membrane in pervaporation, J. Membrane Sci., 447,345-354 (2013)).

The dried organic stream is mixed with two DMSO solutions and entersreactor 412. In some embodiments, the reactor 412 may be amembrane-based reactor, e.g., the PFTR of FIG. 5 . To the organicsolution exiting reactor 412, successive streams of water and tert-butylmethyl ether (TBME) are added to the corresponding phase in a L-L MSXdevice to dispense with the subsequent gravity-based phase separator.The organic phase has the product as a crude solution of fluoxetine inTBME. Thus, virtually all of the steps implemented by traditionaldevices used in the system 400 of FIG. 7 can be performed in an improvedmanner with improved results using membrane-based devices, and suchmembrane-based devices can reduce the overall number of devices used bythe system 400.

FIG. 8 is a schematic of membrane-facilitated continuous manufacturingoperation or process 500 for Prexasertib Monolactate Monohydrate. InFIG. 8 , F&D represents filtration and dissolution, HEX represents heatexchanger, L-L represents liquid-liquid, MEC represents membraneevaporator-concentrator, MM represents membrane mixer, MR representsmembrane reactor, MSX represents membrane solvent extraction, PHFACrepresents polymeric hollow fiber antisolvent crystallizer, and PVrepresents pervaporation. FIG. 8 illustrates the concept that manycontinuous API manufacturing processes based on traditionalnonmembrane-based equipment/processes can be efficiently and effectivelyreplaced by membrane-based equipment. Further, the number of equipmentneeded and (sometimes) the number of steps can be significantly reducedby using membrane-based equipment. FIG. 8 essentially shows theprocesses depicted in FIGS. 6B, 6C and 6D can be carried out by themembrane-based devices illustrated in FIG. 8 .

FIG. 9 is a schematic of continuous membrane-facilitated synthesisprocess 600 of fluoxetine hydrochloride (PROZAC®), and FIG. 10 is aschematic of a continuous membrane-facilitated synthetic route forsynthesis of fluoxetine hydrochloride. In FIG. 9 , DMSO representsdimethyl sulfoxide, HEX represents heat exchanger, L-L representsliquid-liquid, MeNH₂ represents methylamine, MR represents membranereactor, PFTR represents pore flow through reactor, MSX representsmembrane solvent extraction, PV represents pervaporation, and TBMErepresents tert-butyl methyl ether. FIG. 9 reinforces the idea proposedherein, i.e., that many continuous API manufacturing processes based ontraditional nonmembrane-based equipment/processes can be efficiently andeffectively replaced by membrane-based equipment. The continuousmanufacturing example of PROZAC™ shown in FIG. 7 using traditionalmanufacturing devices can be replaced conveniently by membrane-baseddevices and processes. Further, the number of equipment needed and(sometimes) the number of steps can be significantly reduced by use ofmembrane-based equipment.

Thus, the exemplary synthesis systems discussed herein incorporate amembrane device into every or virtually every unit used in APImanufacturing process. All units in the system are connected in a serialfashion and operate continuously such that continuous membrane-basedproduction of APIs is achieved. There is no batch processing in thesystem. In general, the heart of any API production system consists ofthe reactors for synthesis of intermediates and finally the API.Typically, quite a few reaction steps are involved in traditional APIsynthesis anywhere from 2, 3, 4 to around 20 reaction steps (or more).The systems discussed herein ensure that each reaction step can becarried out in a membrane reactor in a continuous fashion. Steps relatedto any reaction carried out before introduction to the reactor (such asmixing reactants, heating the feed) or after the reaction (such asquenching or cooling) can be carried out using membrane-based devices.In some embodiments, the membrane reactor itself can carry out suchfunctions. After each reaction, membrane separation steps can be coupledwith the membrane reactor output and separations/purifications of theintermediates/API can be carried out. Use of such system can provide forextraordinary enhancements in reactions in a multistep API synthesis andproduction process employing membrane reactors at every synthesis stepwhich are then supported by membrane separations at each post-reactionprocessing step. All of these steps can be carried out continuously tocontinuously manufacture APIs.

Thus, a membrane-based production process is provided to produce activepharmaceutical ingredients (APIs). Virtually every step in a continuousmulti-step synthesis-based process to produce an API in thepharmaceutical industry can be carried out with a membrane unit insteadof a conventional non-membrane unit. Membrane reactors can achieve asynthesis level not achievable by conventional tubular reactors.Membrane solvent extraction can allow nondispersive solvent extractionwith great efficiency. Membrane pervaporation can be used to selectivelyremove volatile solvents from a mixture. Organic solvent nanofiltrationand organic solvent reverse osmosis can remove solvents and hold backreaction intermediates or the API at room temperature. Membranecrystallizers, membrane mixers, solid hollow fiber, and ceramic tubularexchangers can now carry out the processes of crystallization, mixingand heat exchange respectively much more efficiently than conventionalnon-membrane based devices. For continuous multistep manufacturing ofactive pharmaceutical ingredients (APIs) in the molecular weight rangeof −150-1000 Da, incorporation of such membrane devices at every step ofthe API manufacturing process can overcome many deficiencies of batchmanufacturing of pharmaceuticals as well as those of continuousprocesses using non-membrane devices and processes.

While exemplary embodiments have been described herein, it is expresslynoted that these embodiments should not be construed as limiting, butrather that additions and modifications to what is expressly describedherein also are included within the scope of the invention. Moreover, itis to be understood that the features of the various embodimentsdescribed herein are not mutually exclusive and can exist in variouscombinations and permutations, even if such combinations or permutationsare not made express herein, without departing from the spirit and scopeof the invention.

The invention claimed is:
 1. A method of producing active pharmaceuticalingredients (APIs), comprising: (a) subjecting a reaction mixture withan API precursor to solvent extraction to produce a reactant stream withthe API precursor; (b) concentrating the API precursor in the reactantstream using at least one membrane; (c) carrying out a reaction in amembrane reactor; (d) separating the API precursor from the reactionstream using a separator; and (e) crystallizing the API precursor usinga crystallizer to produce APIs, wherein at least one of a reactor forperforming step (a), the separator of step (d), or the crystallizer ofstep (e) is a membrane-based device.
 2. The method of claim 1,comprising heating, cooling, and/or quenching of solutions containingactive pharmaceutical ingredients using solid hollow fiber heatexchangers.
 3. The method of claim 2, wherein the heat exchangers aremembrane-based.
 4. The method of claim 1, comprising removing impuritiesfrom organic process streams using membrane adsorbers.